In vivo phosphoproteomics analysis reveals the cardiac targets of ß-adrenergic receptor signaling.
Sci Signal
; 6(278): rs11, 2013 Jun 04.
Article
em En
| MEDLINE
| ID: mdl-23737553
ABSTRACT
ß-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting ß-adrenergic receptors (ßARs) and thus decreasing contractility and heart rate. ßARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We used quantitative in vivo phosphoproteomics to identify 670 site-specific phosphorylation changes in murine hearts in response to acute treatment with specific ßAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and integrative analysis of sequence motifs and interaction networks suggested that the kinases AMPK (adenosine 5'-monophosphate-activated protein kinase), Akt, and mTOR (mammalian target of rapamycin) mediate ßAR signaling, in addition to the well-established pathways mediated by PKA (cyclic adenosine monophosphate-dependent protein kinase) and CaMKII (calcium/calmodulin-dependent protein kinase type II). We found specific regulation of phosphorylation sites on six ion channels and transporters that mediate increased ion fluxes at higher heart rates, and we showed that phosphorylation of one of these, Ser(92) of the potassium channel KV7.1, increased current amplitude. Our data set represents a quantitative analysis of phosphorylated proteins regulated in vivo upon stimulation of seven-transmembrane receptors, and our findings reveal previously unknown phosphorylation sites that regulate myocardial contractility, suggesting new potential targets for the treatment of heart disease and hypertension.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Transdução de Sinais
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Receptores Adrenérgicos beta
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Proteômica
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Coração
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article